Katherine Fitzgerald, Ph.D.

Academic Role: Associate Professor

Faculty Appointment(s) In:
   Infectious Diseases and Immunology
   Medicine

Other Affiliation(s):
   Center for AIDS Research
   Interdisciplinary Graduate Program
   Program in Immunology and Virology

Research Information

Sensing and Signaling in the Innate Immune Response

The innate immune system is essential for the initial detection of invading pathogens and subsequent activation of adaptive immunity. Three classes of germ-line encoded pattern recognition receptors, designated retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), Toll-like receptors (TLRs), and nucleotide oligomerization domain (NOD)-like receptors (NLRs) have been shown to sense microbial components. Very recently novel DNA binding proteins including DNA-dependent activator of Interferons (DAI) and absent in melanoma (AIM2) have also been shown to sense microbial DNA in the cytoplasm of cells. RLRs, TLRs and DAI regulate the transcription of the genes encoding proinflammatory cytokines and/or type I interferons (IFNs) in cell type-specific manners. In contrast the NLRs and AIM2 form large multiprotein complexes in cells termed ‘inflammasomes’ which control the activity of pro-caspase-1 and the maturation of pro-Interleukin (IL-1ß) and pro-IL18 into their active, cleaved and released forms. My lab is focussed on identifying and characterizing these sensors of microbial infection, defining the signal transduction pathways activated downstream of these receptors and understanding the role of these receptors, signaling molecules and the transcription factors they activate in host-defense The long-term objective of our research is to obtain a clear understanding of how the innate immune response functions and the interplay between innate immune signaling pathways and microbial pathogens. Such studies are likely to reveal novel therapeutic and immune-modulation strategies to eliminate acute and chronic viral and bacterial infections.

Publications

1. Hornung, V., Ablasser, A., Charrel-Dennis, M., Bauernfeind, F., Horvath, G., Caffrey, D., Latz E., and K. A. Fitzgerald. 2009. AIM2 recognizes cytosolic dsDNA and forms a caspase-1 activating inflammasome with ASC. Nature (in press).

2. Hornung, V., F. Bauernfeind, A. Halle, E. O. Samstad, H. Kono, K. L. Rock, K. A. Fitzgerald, and E. Latz. 2008. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nature immunology. 18604214

3. Halle, A., V. Hornung, G. C. Petzold, C. R. Stewart, B. G. Monks, T. Reinheckel, K. A. Fitzgerald, E. Latz, K. J. Moore, and D. T. Golenbock. 2008. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nature immunology. 18604209

4. Chessler, A. D., L. R. Ferreira, T. H. Chang, K. A. Fitzgerald, and B. A. Burleigh. 2008. A novel IFN regulatory factor 3-dependent pathway activated by trypanosomes triggers IFN-beta in macrophages and fibroblasts. J Immunol 181:7917-7924. 19017982

5. Chen, W., S. S. Lam, H. Srinath, Z. Jiang, J. J. Correia, C. A. Schiffer, K. A. Fitzgerald, K. Lin, and W. E. Royer, Jr. 2008. Insights into interferon regulatory factor activation from the crystal structure of dimeric IRF5. Nature structural & molecular biology 15:1213-1220. 18836453

6. Charrel-Dennis, M., E. Latz, K. A. Halmen, P. Trieu-Cuot, K. A. Fitzgerald, D. L. Kasper, and D. T. Golenbock. 2008. TLR-independent type I interferon induction in response to an extracellular bacterial pathogen via intracellular recognition of its DNA. Cell Host Microbe 4:543-554. 19064255

7. Balkhi, M. Y., K. A. Fitzgerald, and P. M. Pitha. 2008. Functional regulation of MyD88-activated interferon regulatory factor 5 by K63-linked polyubiquitination. Mol Cell Biol 28:7296-7308. 18824541

8. Severa, M., E. M. Coccia, and K. A. Fitzgerald 2006. Toll-like receptor-dependent and -independent viperin gene expression and counter-regulation by PRDI-binding factor-1/BLIMP1. The Journal of biological chemistry 281:26188-26195. 16849320

9. Rowe, D. C., A. F. McGettrick, E. Latz, B. G. Monks, N. J. Gay, M. Yamamoto, S. Akira, L. A. O'Neill, K. A. Fitzgerald, and D. T. Golenbock. 2006. The myristoylation of TRIF-related adaptor molecule is essential for Toll-like receptor 4 signal transduction. Proc Natl Acad Sci U S A 103:6299-6304. 16603631

10. Schoenemeyer, A., B. J. Barnes, M. E. Mancl, E. Latz, N. Goutagny, P. M. Pitha, K. A. Fitzgerald, and D. T. Golenbock. 2005. The interferon regulatory factor, IRF5, is a central mediator of toll-like receptor 7 signaling. The Journal of biological chemistry 280:17005-17012. 15695821

11. Rothenfusser, S., N. Goutagny, G. DiPerna, M. Gong, B. G. Monks, A. Schoenemeyer, M. Yamamoto, S. Akira, and K. A. Fitzgerald. 2005. The RNA helicase Lgp2 inhibits TLR-independent sensing of viral replication by retinoic acid-inducible gene-I. J Immunol 175:5260-5268. 16210631

12. McWhirter, S. M., K. A. Fitzgerald, J. Rosains, D. C. Rowe, D. T. Golenbock, and T. Maniatis. 2004. IFN-regulatory factor 3-dependent gene expression is defective in Tbk1-deficient mouse embryonic fibroblasts. Proc Natl Acad Sci U S A 101:233-238. 14679297

13. K. A. Fitzgerald, D. C. Rowe, B. J. Barnes, D. R. Caffrey, A. Visintin, E. Latz, B. Monks, P. M. Pitha, and D. T. Golenbock. 2003. LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF. J Exp Med 198:1043-1055. 14517278

14. K. A. Fitzgerald, S. M. McWhirter, K. L. Faia, D. C. Rowe, E. Latz, D. T. Golenbock, A. J. Coyle, S. M. Liao, and T. Maniatis. 2003. IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nature immunology 4:491-496. 12692549

15. K. A. Fitzgerald, E. M. Palsson-McDermott, A. G. Bowie, C. A. Jefferies, A. S. Mansell, G. Brady, E. Brint, A. Dunne, P. Gray, M. T. Harte, D. McMurray, D. E. Smith, J. E. Sims, T. A. Bird, and L. A. O'Neill. 2001. Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature 413:78-83. 11544529

Rotation projects are available in the following areas:

1. Examining the role of AIM2 in the innate immune response to Vaccinia Virus, Herpes Simplex Virus and Cytomegalovirus

2. Examining the role of AIM2 in the innate immune response to cytosolic bacteria (e.g. Listeria monocytogenes).

3. Defining the role of BLIMP1, a transcriptional repressor which shares DNA binding site specificity with members of the IRF family in the innate immune response.

Personnel

Lisa Waggoner, Research Assistant

Shruti Sharma, Post-Doctoral Fellow

Zhaozhao Jiang, Graduate Student

Sandhya Ganesan, Graduate Student

Biography

Kate Fitzgerald received her B.Sc. in 1995 from University College Cork, Ireland, and her Ph.D. in 1999 from Trinity College Dublin, Ireland. From 1999 to 2001, she was a post-doctoral fellow in the Department of Biochemistry at Trinity College Dublin, where her work was supported by a fellowship from the European Union. Dr. Fitzgerald joined the Division of Infectious Disease at the University of Massachusetts Medical School as a recipient of a Wellcome Trust International Award in 2001. In 2004 she joined the Faculty as an Assistant Professor and is currently Associate Professor of Medicine.

Office: LRB 309
Phone: 508-856-6518
Fax: 508-856-5463
E-mail: Katherine.Fitzgerald@umassmed.edu
Keywords: Infectious Disease, Inflammation/Inflammatory Diseases

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